Recent research suggests that obesity and diet induce inflammation in adipose tissue, which may enhance the development of type 2 diabetes mellitus (T2DM) and insulin resistance (IR). Epidemiological studies have demonstrated that exposure to air pollution, in particular ambient fine particulate matter (<2.5 ?m, PM2.5), is associated with increased cardiovascular diseases. Our recent data have shown that short-term exposure to inhaled PM2.5 results in vascular inflammation in atherosclerosis in adult mice. This inflammatory response may represent a key integrative pathway that is one of the fundamental mechanisms for atherosclerosis, hypertension, and IR. To investigate the effects of exposure to PM2.5 on adiposity and IR development, we hypothesize that PM2.5 exposure induces adiposity and IR development that is exaggerated by fat-rich diet through C-C motif chemokine ligand (CCL)2-mediated adipose tissue macrophage (ATM) infiltration and increased pro-inflammatory classically activated (M1)/ decreased anti-inflammatory alternatively activated (M2) macrophage phenotypic gene change in visceral adipose tissue (VAT) in mice. To test this hypothesis, in the first specific aim, we will investigate the effect of exposure to PM2.5 on mice in a whole body exposure system from early age (4 weeks old) for 8 or 24 weeks, examining outcomes of adiposity, macrophage infiltration in VAT, IR, and vascular dysfunction in C57BL/6 for mice fed with either low fat or high fat chow. Intraperitoneal glucose tolerance test, magnetic resonance imaging on body fat mass, myograph on vasomotor tone change, morphology and immunoblotting of skeletal muscle, liver, subcutaneous and visceral adipose tissues on IR, and adipocyte number and size quantification will be performed. In the second specific aim, we will determine whether the adiposity and IR development induced by PM2.5 exposure is associated with macrophage infiltration and M1/M2 phenotypic gene expression change in VAT. In the final specific aim, we will illustrate that PM2.5-induced adiposity and IR is mediated by CCL2 via ATM activation, recruitment, and M1/M2 phenotypic gene expression change in the VAT in C-C motif chemokine receptor (CCR)2-/- mice. By using state-of-the-art real world PM2.5 exposure in conjunction with the latest advances in inflammatory mechanisms, this proposal provides an unprecedented opportunity to elucidate physiologically relevant mechanisms responsible for the effects of PM2.5 on the development of obesity, T2DM, and IR, each of which has significant impact on public health. PUBLIC HEALTH RELEVANCE: Air pollution and obesity each cause significant public health burdens. This study will examine whether exposure to ambient fine particulate pollution combined with a high fat diet will act together to cause increased obesity, type 2 diabetes mellitus, and insulin resistance.